Matrix Metalloproteinases and Bladder Cancer: What is New?

Urothelial bladder cancer represents a heterogeneous disease with divergent pathways of tumorigenesis. Tumor invasion and progression are a multifactorial process promoted by microenvironmental changes that include overexpression of matrix metalloproteinases (MMPs). Recent data clearly challenge the classic dogma that MMPs promote metastasis only by modulating the remodeling of extracellular matrix. Indeed, MMPs have also been attributed as an impact on tumor cell behavior in vivo as a consequence of their ability to cleave growth factors, cell surface receptors, cell adhesion molecules, and chemokines/cytokines. Levels of the different MMPs can be measured in several sample types, including tissue, blood (serum and plasma), and urine, and using different methodologies, such as immunohistochemistry, real-time PCR, western and northern blot analyses, enzyme-linked immunosorbent assay, and zymography. Several MMPs have been identified as having potential diagnostic or prognostic utility, whether alone or in combination with cytology. Although MMP inhibitors have shown limited efficacy, advances in the understanding of the complex physiologic and pathologic roles of MMPs might permit the development of new MMP-specific and tumor-specific therapies. In this paper we update the understanding of MMPs based on a systematic PubMed search encompassing papers published up to December 2011. 1. Introduction Urothelial bladder carcinoma (UBC) represents a heterogeneous disease with high morbidity and mortality. It ranks fifth among all cancers in the Western world, and there are 336,000 new cases and 132,000 deaths annually worldwide [1]. UBC mainly affects the elderly, with the peak incidence occurring after the age of 50. It is more common in males, in white people, and in developing countries. Most cases are sporadic, so a familial history is lacking. Cigarette smoking is a major risk factor. Other risk factors include exposure to arylamines, radiotherapy to adjacent organs, alkylating chemotherapeutic agents, and chronic inflammation [2]. There are two theories regarding the multifocal nature of urothelial carcinoma: “field cancerization” and “monoclonality” [3]. Genetic studies support the monoclonality theory and indicate that tumor cells spread from their origins to multiple sites by intraepithelial or intraluminal seeding. Non-muscle-invasive (NMI) disease accounts for ca. 70% of cases. Despite treatment with BCG, high-grade NMI tumors are associated with a high risk of recurrence and progression. Approximately 20% of primary diagnosed UBCs are muscle